Cinnamic amide derivatives containing quinazoline and piperazine units, and preparation method and application thereof

Abstract

The application belongs to the field of pesticides, and discloses a compound with the structure of formula I, a preparation method of the compound, and the compound is prepared by the following steps: reacting piperazine and piperazine dihydrochloride in hot ethanol, then sequentially reacting with different benzyl chlorides and sodium hydroxide solution to obtain corresponding monosubstituted piperazine; subsequently, methyl anthranilate is sequentially reacted with formamide, sulfoxide, coumarin molecules hydrolyzed by sodium hydroxide and monosubstituted piperazine to obtain the cinnamic acid amide derivative containing quinazoline and piperazine units; the cinnamic acid amide derivative containing quinazoline and piperazine units is a novel compound, has inhibitory effect on botrytis cinerea, sclerotinia sclerotiorum, fusarium graminearum or rhizoctonia solani, and can be used for preventing and treating plant diseases caused by fungi.

Description

Technical Field

[0001] This invention belongs to the field of pesticides, specifically relating to a cinnamamide derivative containing quinazoline and piperazine units, its preparation method, and its application. Background Technology

[0002] As a global threat, existing plant diseases seriously threaten the yield and quality of agricultural products, becoming a significant factor affecting agricultural development. Among these, diseases caused by plant pathogenic fungi account for 70%-80% of crop diseases, resulting in annual crop yield reductions of up to 10% and direct or indirect agricultural economic losses exceeding US$200 billion. Furthermore, these pathogens can be spread through air, soil, and water, increasing the difficulty of prevention. Currently, chemical fungicides remain the primary means of treating plant fungal infections. However, the long-term overuse of existing fungicides has not only led to drug resistance in many pathogens but also resulted in serious problems such as pesticide residues and negative environmental impacts. Therefore, the development of green, efficient, and low-toxicity fungicides is urgently needed. Summary of the Invention

[0003] Objectives of the invention: The first objective of this invention is to provide a cinnamamide derivative containing quinazoline and piperazine units; the second objective of this invention is to provide a method for preparing the cinnamamide derivative containing quinazoline and piperazine units; the third objective of this invention is to provide the application of the cinnamamide derivative containing quinazoline and piperazine units in the prevention and control of plant pathogenic fungal diseases.

[0004] Technical solution: The present invention provides a cinnamamide derivative containing quinazoline and piperazine units, with the structural formula shown in Figure I:

[0005]

[0006] In the formula:

[0007] R 1 Selected from hydrogen, 2-methyl, 3-methyl, 4-methyl, 3-methoxy, 3-bromo, 4-bromo, 4-fluoro, 3-fluoro, 3-cyano, 2-chloro, 3-chloro, 4-chloro, 4-nitro;

[0008] R 2 Selected from hydrogen, 3-(3-methylbut-2-en-1-yl)-4-methoxy.

[0009] The method for preparing the cinnamamide derivative containing quinazoline and piperazine units according to the present invention includes the following steps: piperazine reacts with piperazine dihydrochloride in hot ethanol, and then reacts sequentially with different benzyl chloride and sodium hydroxide solutions to obtain the corresponding monosubstituted piperazine; subsequently, methyl anthranilate reacts sequentially with formamide, thionyl chloride, coumarin molecules hydrolyzed with sodium hydroxide, and the monosubstituted piperazine to obtain the cinnamamide derivative containing quinazoline and piperazine units. The synthetic route is as follows:

[0010]

[0011] The application of the cinnamamide derivative containing quinazoline and piperazine units described in this invention in the prevention and control of plant pathogenic fungal diseases.

[0012] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The cinnamamide derivative containing quinazoline and piperazine units of the present invention is a new type of compound; (2) The preparation method of the cinnamamide derivative containing quinazoline and piperazine units of the present invention is simple to operate and the raw materials are readily available; (3) The cinnamamide derivative containing quinazoline and piperazine units of the present invention has an inhibitory effect on Botrytis cinerea, Sclerotinia sclerotiorum, Fusarium graminearum and Rhizoctonia solani, and has the application prospect of being developed as a potential agricultural fungicide. Attached Figure Description

[0013] Figure 1 The 1H NMR spectrum of the cinnamamide derivative containing quinazoline and piperazine units prepared in Example 4;

[0014] Figure 2 The carbon spectrum of the cinnamamide derivative containing quinazoline and piperazine units prepared in Example 4;

[0015] Figure 3 The high-resolution mass spectrum of the cinnamamide derivative containing quinazoline and piperazine units prepared in Example 4 is shown. Detailed Implementation

[0016] The technical solution of the present invention will be further described below with reference to the embodiments.

[0017] Example 1

[0018] The cinnamamide derivative I1,R containing quinazoline and piperazine units of the present invention 1 =H,R 2=H, chemical name (E)-1-(4-benzylpiperazin-1-yl)-3-(2-(quinazolin-4-oxo)phenyl)prop-2-en-1-one, English name (E)-1-(4-benzylpiperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0019]

[0020] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0021]

[0022] 5.80 mmol of piperazine and 11.61 mmol of piperazine dihydrochloride were added sequentially to 65 mL of ethanol. After stirring and mixing, the mixture was heated to 75 °C and refluxed for about 2 h to obtain a solution containing piperazine monohydrochloride (intermediate 1).

[0023] Step 2: Synthesis of 1-benzylpiperazine (intermediate 2a)

[0024]

[0025] Add 5.8 mmol of benzyl chloride to the solution obtained in the first step, heat to reflux for about 2 hours, filter under reduced pressure, remove excess solvent by vacuum distillation, add 50 mL of purified water to the residue, and wash three times with dichloromethane. Adjust the pH of the resulting aqueous phase to 10 with 5% NaOH, then extract and wash three times with dichloromethane, and evaporate the organic phase to dryness to obtain 1-benzylpiperazine (intermediate 2a).

[0026] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0027]

[0028] Methyl anthranilate (19.85 mmol), formamide (178.61 mmol), and formic acid (19.85 mmol) were added sequentially to a three-necked flask. After stirring and mixing, the mixture was heated to 150 °C and reacted for approximately 5 hours. Subsequently, while still hot, the reaction solution was transferred to a beaker containing water and stirred with a glass rod. A white solid precipitated, and impurities in the filter cake were removed by vacuum filtration and washing with dichloromethane. The resulting filter cake was dried to obtain quinazolin-4(3H)-one (intermediate 3a).

[0029] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0030]

[0031] Quinazoline-4(3H)-one (20.53 mmol), N,N-dimethylformamide (DMF, 10.26 mmol), 1,2-dichloroethane (328.43 mmol), and thionyl chloride (287.38 mmol) were added sequentially to a round-bottom flask, and the mixture was heated to 90 °C and reacted for 3 h. Subsequently, the solvent was removed by vacuum distillation, and an appropriate amount of petroleum ether was added to dissolve the residue. Insoluble impurities were removed by filtration, and the filtrate was further purified by vacuum distillation to remove the petroleum ether, yielding 4-chloroquinazoline (intermediate 4a).

[0032] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0033]

[0034] Coumarin (20.53 mmol) was added to ethanol (65 mL), stirred until clear, and then sodium hydroxide solution (5%, 20.53 mmol) was slowly added. The mixture was heated to reflux for about 5 h, and the solvent was removed by vacuum distillation to obtain sodium 3-(2-oxophenyl)acrylate. Subsequently, 4-chloroquinazoline (21.62 mmol) and sodium 3-(2-oxophenyl)acrylate (14.41 mmol) were added to acetonitrile (65 mL), heated to reflux for about 5 h, and excess solvent was removed by vacuum distillation. Distilled water (100 mL) was added to the residue, and the mixture was extracted and washed three times with dichloromethane. The resulting aqueous phase was adjusted to pH 3 with hydrochloric acid, and a white solid precipitated. This solid was filtered under reduced pressure to obtain 3-(2-(quinazoline-4-oxyphenyl)acrylic acid (intermediate 5a).

[0035] Step 6: Synthesis of (E)-1-(4-benzylpiperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I1)

[0036]

[0037] 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (2.05 mmol), TBTU (2.46 mmol), and triethylamine (6.16 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for about 30 min. Then, 1-benzylpiperazine (2.46 mmol) dissolved in dichloromethane (15 mL) was added to the reaction system, and the reaction was carried out at room temperature for about 5 h. Excess solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain the target compound I1.

[0038] The target compound I1 was a yellow oil with a yield of 74%. 1H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.43 (dd, J=8.3, 1.5Hz, 1H), 8.01 (dt, J= 8.5, 0.9Hz, 1H), 7.91 (ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.74-7.65 (m, 3H), 7.47 ( td, J=7.8, 1.6Hz, 1H), 7.38-7.27 (m, 6H), 7.24 (d, J=1.3Hz, 1H), 6.87 (d, J= 15.6Hz, 1H), 3.62 (s, 2H), 3.46 (s, 2H), 3.40 (s, 2H), 2.32 (d, J=49.4Hz, 4H); 13 C NMR (100MHz, CDCl3) δ166.73, 164.98, 154.18, 151.80, 150.74, 137.45, 136.06, 134.34, 130.66, 129.13, 128.66, 128.43, 1 28.35, 128.08, 127.89, 127.33, 126.56, 123.51, 123.37, 119.89, 116.16, 77.26, 62.76, 53.44, 53.06, 52.59, 45.72, 42.07.

[0039] Example 2

[0040] The cinnamamide derivative I2,R containing quinazoline and piperazine units of the present invention 1 =H,R 2 = 4-methoxy-3-(3-methylbut-2-en-1-yl), chemically named (E)-1-(4-benzylpiperazin-1-yl)-3-(4-methoxy-3-(3-methylbut-2-en-1-yl)-2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-benzylpiperazin-1-yl)-3-(4-methoxy-3-(3-methylbut-2-en-1-yl)-2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0041]

[0042] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0043] As in the first step of Example 1.

[0044] Step 2: Synthesis of 1-benzylpiperazine (intermediate 2a)

[0045] As in step 2 of Example 1.

[0046] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0047] As in step 3 of Example 1.

[0048] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0049] As in step four of Example 1.

[0050] Step 5: Synthesis of 3-(4-methoxy-3-(3-methylbut-2-en-1-yl)-2-(quinazolin-4-oxy)phenyl)acrylic acid (intermediate 5b)

[0051]

[0052] As in step 5 of Example 1, the difference is that osthol is used as the reactant.

[0053] Step 6: Synthesis of (E)-1-(4-benzylpiperazin-1-yl)-3-(4-methoxy-3-(3-methylbut-2-en-1-yl)-2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I2)

[0054] As in step 6 of Example 1, the difference is that 3-(4-methoxy-3-(3-methylbut-2-en-1-yl)-2-(quinazolin-4-oxy)phenyl)acrylic acid is used as the reactant.

[0055] The target compound I2 was a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 8.44 (dd, J=8.2, 1.4Hz, 1H), 8.00 (d, J=8.4Hz, 1H), 7.90 (ddd, J=8.5, 7.0, 1.5Hz, 1H), 7.67 (ddd, J=8.2, 7.0, 1.2Hz, 1H), 7.57-7.48 (m, 2H), 7.34-7.30 (m, 2H), 7.28 (dd, J=4. 9, 1.9Hz, 4H), 6.89 (d, J=8.7Hz, 1H), 6.69 (d, J=15.5Hz, 1H), 5.11-4.91 (m, 1H), 3.91 (s, 3H), 3.57 (s, 2H ), 3.44 (s, 2H), 3.40-3.25 (m, 3H), 2.26 (d, J = 66.6Hz, 4H), 1.45 (d, J = 1.5Hz, 3H), 1.25 (d, J = 1.3Hz, 3H); 13C NMR (101MHz, CDCl3) δ166.39, 165.41, 159.58, 154.41, 151.69, 149.86, 1 37.39, 136.96, 134.27, 131.89, 129.16, 128.34, 128.03, 127.75, 127.33 ,126.97,123.66,123.48,121.66,121.37,117.13,115.84,108.90,62.7 5, 55.91, 52.90, 45.84, 45.53, 41.96, 29.70, 25.52, 23.49, 17.38, 8.63.

[0056] Example 3

[0057] The cinnamamide derivative I3,R containing quinazoline and piperazine units of the present invention 1 =2-Me,R 2 =H, chemically named (E)-1-(4-(2-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(2-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0058]

[0059] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0060] As in the first step of Example 1.

[0061] Step 2: Synthesis of 1-(2-methylbenzyl)piperazine (intermediate 2b)

[0062]

[0063] As in step 2 of Example 1, the difference is that 2-methylbenzyl chloride is used as the reactant.

[0064] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0065] As in step 3 of Example 1.

[0066] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0067] As in step four of Example 1.

[0068] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0069] As in step 5 of Example 1.

[0070] Step 6: Synthesis of (E)-1-(4-(2-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I3)

[0071] As in step 6 of Example 1, the difference is that 1-(2-methylbenzyl)piperazine is used as the reactant.

[0072] The target compound I3 was a white solid with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ8.73 (d, J=1.7Hz, 1H), 8.43 (d, J=8.2Hz, 1H), 8.01 (d, J =8.4Hz, 1H), 7.90 (t, J = 7.7Hz, 1H), 7.75-7.64 (m, 3H), 7.47 (t, J = 7.8Hz, 1H) , 7.36 (d, J=7.6Hz, 1H), 7.25-7.11 (m, 5H), 6.88 (d, J=15.6Hz, 1H), 3.59 (s, 2 H), 3.43-3.30 (m, 4H), 2.43-2.35 (m, 2H), 2.33 (d, J=1.7Hz, 3H), 2.24 (s, 2H); 13 C NMR (101MHz, CDCl3) δ166.74, 164.97, 154.18, 151.82, 150.76, 137.56, 136.00, 135.74, 134.33, 130.64, 130.39, 129.88, 128.6 9, 128.44, 128.08, 127.89, 127.33, 126.56, 125.56, 123.51, 123.37, 119.97, 116.17, 60.65, 53.08, 52.72, 45.85, 42.21, 19.23.

[0073] Example 4

[0074] The cinnamamide derivative I4,R containing quinazoline and piperazine units described in this invention 1 =3-Me,R 2=H, chemical name (E)-1-(4-(3-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0075]

[0076] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0077] As in the first step of Example 1.

[0078] Step 2: Synthesis of 1-(3-methylbenzyl)piperazine (intermediate 2c)

[0079]

[0080] As in step 2 of Example 1, the difference is that 3-methylbenzyl chloride is used as the reactant.

[0081] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0082] As in step 3 of Example 1.

[0083] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0084] As in step four of Example 1.

[0085] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0086] As in step 5 of Example 1.

[0087] Step 6: Synthesis of (E)-1-(4-(3-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I4)

[0088] As in step 6 of Example 1, the difference is that 1-(3-methylbenzyl)piperazine is used as the reactant.

[0089] The target compound I4 was a white solid with a yield of 55%; H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.43 (dd, J=8.3, 1.4Hz, 1H), 8.01 (d, J=8. 4Hz, 1H), 7.91 (ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.75-7.64 (m, 3H), 7.47 (td, J=7 .7, 1.6Hz, 1H), 7.35 (t, J=7.3Hz, 1H), 7.26-7.18 (m, 2H), 7.11-7.03 (m, 3H), 6.87(d, J=15.6Hz, 1H), 3.62(s, 2H), 3.42(s, 4H), 2.35(s, 5H), 2.26(s, 2H); 13 C NMR (101MHz, CDCl3) δ166.74, 164.97, 154.18, 151.80, 150.74, 137.97, 137.39, 136.03, 134.33, 130.65, 129.87, 128.67, 128.4 1, 128.21, 128.08, 127.89, 126.56, 126.23, 123.52, 123.37, 119.90, 116.17, 53.44, 53.12, 52.62, 45.72, 42.08, 38.63, 21.40.

[0090] Example 5

[0091] The cinnamamide derivative I5,R containing quinazoline and piperazine units described in this invention 1 =4-Me,R 2 =H, chemically named (E)-1-(4-(4-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(4-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0092]

[0093] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0094] As in the first step of Example 1.

[0095] Step 2: Synthesis of 1-(4-methylbenzyl)piperazine (intermediate 2d)

[0096]

[0097] As in step 2 of Example 1, the difference is that 4-methylbenzyl chloride is used as the reactant.

[0098] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0099] As in step 3 of Example 1.

[0100] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0101] As in step four of Example 1.

[0102] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0103] As in step 5 of Example 1.

[0104] Step 6: Synthesis of (E)-1-(4-(4-methylbenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I5)

[0105] As in step 6 of Example 1, the difference is that 1-(4-methylbenzyl)piperazine is used as the reactant.

[0106] The target compound I5 was a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.42 (dd, J=8.3, 1.5Hz, 1H), 8.00 (d, J=8. 4Hz, 1H), 7.91 (ddd, J=8.5, 7.0, 1.5Hz, 1H), 7.74-7.63 (m, 3H), 7.46 (td, J=7 .7, 1.6Hz, 1H), 7.38-7.30 (m, 1H), 7.23 (d, J=1.3Hz, 1H), 7.13 (q, J=8.1Hz, 4 H), 6.86 (d, J=15.6Hz, 1H), 3.60 (s, 2H), 3.40 (d, J=9.6Hz, 4H), 2.33 (s, 7H); 13 C NMR (101MHz, CDCl3) δ166.74, 164.96, 154.19, 151.81, 150.74, 136.93, 136.00, 134.42, 134.33, 130.64, 129.10, 129.01, 1 28.68, 128.41, 128.08, 127.89, 126.56, 123.52, 123.37, 119.93, 116.17, 77.27, 62.51, 53.03, 52.52, 45.77, 42.11, 21.13.

[0107] Example 6

[0108] The cinnamamide derivative I6,R containing quinazoline and piperazine units of the present invention 1 =3-OMe,R 2 =H, chemically named (E)-1-(4-(3-methoxybenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-methoxybenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0109]

[0110] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0111] As in the first step of Example 1.

[0112] Step 2: Synthesis of 1-(3-methoxybenzyl)piperazine (intermediate 2e)

[0113]

[0114] As in step 2 of Example 1, the difference is that 3-methoxybenzyl chloride is used as the reactant.

[0115] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0116] As in step 3 of Example 1.

[0117] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0118] As in step four of Example 1.

[0119] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0120] As in step 5 of Example 1.

[0121] Step 6: Synthesis of (E)-1-(4-(3-methoxybenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I6)

[0122] As in step 6 of Example 1, the difference is that 1-(3-methoxybenzyl)piperazine is used as the reactant.

[0123] The target compound I6 was a white solid with a yield of 75%.1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.43 (dd, J=8.3, 2.5Hz, 1H), 8.01 (dd, J=8.5 , 2.9Hz, 1H), 7.96-7.86(m, 1H), 7.75-7.63(m, 3H), 7.47(q, J=7.1Hz, 1H), 7.35( q, J=7.3Hz, 1H), 7.25-7.18 (m, 2H), 6.91-6.83 (m, 3H), 6.80 (dd, J=8.1, 3.1Hz, 1H), 3.84-3.78(m, 3H), 3.61(s, 2H), 3.48-3.36(m, 4H), 2.31(d, J=49.4Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.73, 164.97, 159.70, 154.18, 151.80, 150.74, 139.29, 136.02, 134.34, 130.65, 129.29, 128.66, 128.4 2, 128.08, 127.90, 126.56, 123.51, 123.37, 121.37, 119.90, 116.16, 114.63, 112.58, 62.69, 55.23, 53.08, 52.63, 45.76.42.10.

[0124] Example 7

[0125] The cinnamamide derivative I7,R containing quinazoline and piperazine units of the present invention 1 =3-Br,R 2 =H, chemically named (E)-1-(4-(3-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0126]

[0127] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0128] As in the first step of Example 1.

[0129] Step 2: Synthesis of 1-(3-bromobenzyl)piperazine (intermediate 2f)

[0130]

[0131] As in step 2 of Example 1, the difference is that 3-bromobenzyl chloride is used as the reactant.

[0132] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0133] As in step 3 of Example 1.

[0134] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0135] As in step four of Example 1.

[0136] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0137] As in step 5 of Example 1.

[0138] Step 6: Synthesis of (E)-1-(4-(3-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I7)

[0139] As in step 6 of Example 1, the difference is that 1-(3-bromobenzyl)piperazine is used as the reactant.

[0140] The target compound I7 was a white solid with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.43 (dd, J=8.3, 1.4Hz, 1H), 8.01 (d, J=8.4Hz, 1H), 7.91 (ddd, J=8.5, 7.0, 1.5Hz, 1H), 7.75-7.65 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.32 (m, 2H), 7.25-7.14 (m, 3H), 6.87 (d, J=15.6Hz, 1H), 3.61 (s, 2H), 3.39 (d, J=9.5Hz, 4H), 2.29 (d, J=56.9Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.72, 164.99, 154.19, 151.81, 150.75, 140.17, 136.14, 134.33, 131.89, 130.67, 130.42, 129.92, 12 8.64, 128.49, 128.10, 127.89, 127.57, 126.57, 123.50, 123.38, 122.54, 119.86, 116.16, 62.06, 52.99, 52.63, 45.68, 42.05.

[0141] Example 8

[0142] The cinnamamide derivative I8,R containing quinazoline and piperazine units of the present invention 1 =4-Br,R 2 =H, chemical name (E)-1-(4-(4-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(4-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0143]

[0144] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0145] As in the first step of Example 1.

[0146] Step 2: Synthesis of 1-(4-bromobenzyl)piperazine (intermediate 2g)

[0147]

[0148] As in step 2 of Example 1, the difference is that 4-bromobenzyl chloride is used as the reactant.

[0149] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0150] As in step 3 of Example 1.

[0151] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0152] As in step four of Example 1.

[0153] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0154] As in step 5 of Example 1.

[0155] Step 6: Synthesis of (E)-1-(4-(4-bromobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I8)

[0156] As in step 6 of Example 1, the difference is that 1-(4-bromobenzyl)piperazine is the reactant.

[0157] The target compound I8 was a yellow solid with a yield of 65%. 1H NMR (500MHz, CDCl3) δ8.75 (s, 1H), 8.45 (dd, J=8.3, 1.4Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 7.95 (ddd, J=8.5, 7.0, 1.5Hz, 1H), 7.79-7.68 (m, 3H), 7.54-7.45 (m, 3H), 7.38 (td, J=7.7, 1.3Hz, 1H), 7.27 (d, J=1.2Hz, 1H), 7.25-7.15 (m, 2 H), 6.89 (d, J=15.6Hz, 1H), 3.53 (d, J=102.6Hz, 6H), 2.32 (d, J=62.2Hz, 4H); 13 CNMR (101MHz, CDCl3) δ170.19, 166.73, 165.00, 154.18, 151.81, 150.75, 136.73, 136.11, 134.33, 131.46, 130.67, 128.64, 1 28.39, 128.08, 127.89, 126.56, 123.51, 123.36, 121.10, 119.82, 116.16, 77.24, 76.90, 62.01, 53.01, 52.54, 45.72, 42.09.

[0158] Example 9

[0159] The cinnamamide derivative I9,R containing quinazoline and piperazine units of the present invention 1 =4-F,R 2 =H, chemical name (E)-1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0160]

[0161] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0162] As in the first step of Example 1.

[0163] Step 2: Synthesis of 1-(4-fluorobenzyl)piperazine (intermediate 2h)

[0164]

[0165] As in step 2 of Example 1, the difference is that 4-fluorobenzyl chloride is used as the reactant.

[0166] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0167] As in step 3 of Example 1.

[0168] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0169] As in step four of Example 1.

[0170] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0171] As in step 5 of Example 1.

[0172] Step 6: Synthesis of (E)-1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I9)

[0173] As in step 6 of Example 1, the difference is that 1-(4-fluorobenzyl)piperazine is used as the reactant.

[0174] The target compound I9 was a yellow oil with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.43 (dd, J=8.3, 1.4Hz, 1H), 8.01 (d, J=8.4Hz, 1H ), 7.91 (ddd, J=8.5, 6.9, 1.5Hz, 1H), 7.74-7.65 (m, 3H), 7.47 (td, J=7.8, 1.6Hz, 1H) , 7.35 (td, J=7.7, 1.3Hz, 1H), 7.23 (ddt, J=8.7, 5.5, 2.8Hz, 3H), 7.04-6.97 (m, 2H), 6.87 (d, J=15.6Hz, 1H), 3.58 (d, J=18.2Hz, 2H), 3.41 (s, 4H), 2.29 (d, J=48.8Hz, 4H); 13C NMR (101MHz, CDCl3) δ166.73, 165.00, 163.33, 160.89, 154.18, 151.80, 150.75, 136.09, 134.32, 133.32, 130.67, 130.57, 130 .49, 128.65, 128.41, 128.07, 127.89, 126.56, 123.51, 123.37, 119.85, 116.16, 115.25, 115.04, 53.43, 52.52, 45.71, 42.07.

[0175] Example 10

[0176] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 10 R 1 =3-F,R 2 =H, chemically named (E)-1-(4-(3-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0177]

[0178] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0179] As in the first step of Example 1.

[0180] Step 2: Synthesis of 1-(3-fluorobenzyl)piperazine (intermediate 2i)

[0181]

[0182] As in step 2 of Example 1, the difference is that 3-fluorobenzyl chloride is used as the reactant.

[0183] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0184] As in step 3 of Example 1.

[0185] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0186] As in step four of Example 1.

[0187] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0188] As in step 5 of Example 1.

[0189] Step 6: (E)-1-(4-(3-fluorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I) 10 Synthesis of )

[0190] As in step 6 of Example 1, the difference is that 1-(3-fluorobenzyl)piperazine is used as the reactant.

[0191] Target compound I 10 It is a white solid with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.49-8.39 (m, 1H), 8.01 (d, J=8.4Hz, 1H), 7.95-7.8 8 (m, 1H), 7.76-7.64 (m, 3H), 7.48 (td, J=7.7, 1.6Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 7.29 ( d, J=8.0Hz, 1H), 7.24 (s, 1H), 7.03 (dd, J=10.2, 4.2Hz, 2H), 6.95 (td, J=8.5, 2.7Hz, 1H ), 6.87 (d, J = 15.6Hz, 1H), 3.62 (s, 2H), 3.42 (d, J = 16.5Hz, 4H), 2.31 (d, J = 52.2Hz, 4H); 3 C NMR (101MHz, CDCl3) δ166.74, 165.02, 164.18, 161.74, 154.17, 151.77, 15 0.74, 140.40, 140.33, 136.12, 134.36, 130.70, 129.82, 129.74, 128.63, 12 8.45, 128.06, 127.91, 126.58, 124.50, 124.47, 123.51, 123.37, 119.83, 11 6.15, 115.77, 115.56, 114.30, 114.09, 62.11, 53.02, 52.58, 45.71, 42.06.

[0192] Example 11

[0193] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 11 R 1 =3-CN,R 2=H, chemical name (E)-1-(4-(3-cyanobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-cyanobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0194]

[0195] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0196] As in the first step of Example 1.

[0197] Step 2: Synthesis of 1-(3-cyanobenzyl)piperazine (intermediate 2j)

[0198]

[0199] As in step 2 of Example 1, the difference is that 3-cyanobenzyl chloride is used as the reactant.

[0200] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0201] As in step 3 of Example 1.

[0202] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0203] As in step four of Example 1.

[0204] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0205] As in step 5 of Example 1.

[0206] Step 6: (E)-1-(4-(3-cyanobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (Target compound I) 11 Synthesis of )

[0207] As in step 6 of Example 1, the difference is that 1-(3-cyanobenzyl)piperazine is used as the reactant.

[0208] Target compound I 11 It is a white solid with a yield of 55%. 1H NMR (400MHz, CDCl3) δ8.71 (d, J=1.4Hz, 1H), 8.43 (dd, J=8.4, 1.6Hz, 1H), 8.01 (d, J=8.4Hz, 1H), 7.92 (ddd, J=8.5, 6.9, 1.5Hz, 1H), 7.74-7.65 (m, 3H), 7.61 (d, J=1.9Hz, 1H), 7.51 (ddd d, J=20.9, 15.5, 7.6, 1.6Hz, 3H), 7.42 (t, J=7.7Hz, 1H), 7.35 (t, J=7.7Hz, 1H), 7.26-7.23 ( m, 1H), 6.86 (d, J = 15.6Hz, 1H), 3.62 (s, 2H), 3.43 (d, J = 23.2Hz, 4H), 2.30 (d, J = 45.6Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.74, 165.04, 154.17, 151.79, 150.76, 139.48, 136.22, 134.35, 133.26, 132.31, 131.04, 130.74, 129.20 , 128.60, 128.39, 128.06, 127.91, 126.58, 123.52, 123.37, 119.73, 118.82, 116.15, 112.55, 61.76, 53.04, 52.59, 45.67, 42.01.

[0209] Example 12

[0210] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 12 R 1 =4-CN,R 2 =H, chemical name is (E)-1-(4-(4-cyanobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name is (E)-1-(4-(4-cyanobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula is as follows:

[0211]

[0212] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0213] As in the first step of Example 1.

[0214] Step 2: Synthesis of 1-(4-cyanobenzyl)piperazine (intermediate 2k)

[0215]

[0216] As in step 2 of Example 1, the difference is that 4-cyanobenzyl chloride is used as the reactant.

[0217] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0218] As in step 3 of Example 1.

[0219] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0220] As in step four of Example 1.

[0221] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0222] As in step 5 of Example 1.

[0223] Step 6: (E)-4-((4-(3-(2-(quinazolin-4-oxy)phenyl)acryloyl)piperazin-1-yl)methyl)benzonitrile (target compound I) 12 Synthesis of )

[0224] As in step 6 of Example 1, the difference is that 1-(4-cyanobenzyl)piperazine is used as the reactant.

[0225] Target compound I 12 It is a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.44 (dd, J=8.4, 1.5Hz, 1H), 8.02 (d, J=8.4H z, 1H), 7.93 (tt, J=8.3, 1.2Hz, 1H), 7.77-7.66 (m, 3H), 7.62 (d, J=2.0Hz, 1H), 7. 58-7.40 (m, 4H), 7.36 (t, J=7.6Hz, 1H), 7.26 (dd, J=7.9, 1.1Hz, 1H), 6.88 (d, J= 15.6Hz, 1H), 3.69-3.57 (m, 2H), 3.45 (d, J=22.5Hz, 4H), 2.31 (d, J=45.6Hz, 4H); 13C NMR (101MHz, CDCl3) δ166.74, 165.05, 154.15, 151.76, 150.75, 139.45, 136.23, 134.37, 133.28, 132.32, 131.05, 130.76, 129.20 , 128.58, 128.39, 128.04, 127.93, 126.59, 123.52, 123.37, 119.72, 118.83, 116.15, 112.53, 61.76, 53.06, 52.57, 45.65, 42.01.

[0226] Example 13

[0227] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 13 R 1 =2-Cl, R 2 =H, chemical name (E)-1-(4-(2-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(2-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0228]

[0229] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0230] As in the first step of Example 1.

[0231] Step 2: Synthesis of 1-(2-chlorobenzyl)piperazine (intermediate 21)

[0232]

[0233] As in step 2 of Example 1, the difference is that 2-chlorobenzyl chloride is used as the reactant.

[0234] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0235] As in step 3 of Example 1.

[0236] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0237] As in step four of Example 1.

[0238] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0239] As in step 5 of Example 1.

[0240] Step 6: (E)-1-(4-(2-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I) 13 Synthesis of )

[0241] As in step 6 of Example 1, the difference is that 1-(2-chlorobenzyl)piperazine is used as the reactant.

[0242] Target compound I 13 It is a white solid with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.43 (dd, J=8.3, 1.4Hz, 1H), 8.00 (d, J=8.4Hz, 1H ), 7.91 (ddd, J=8.4, 6.9, 1.5Hz, 1H), 7.75-7.65 (m, 3H), 7.47 (td, J=7.7, 1.6Hz, 1H) , 7.40 (dd, J=7.3, 2.0Hz, 1H), 7.35 (ddd, J=7.6, 3.9, 1.4Hz, 2H), 7.25-7.16 (m, 3H), 6.87 (d, J=15.6Hz, 1H), 3.59 (d, J=20.6Hz, 4H), 3.40 (s, 2H), 2.38 (d, J=47.5Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.73, 165.02, 154.18, 151.81, 150.75, 136.05, 135.27, 134.41, 134.33, 130.73, 130.65, 129.57, 12 8.66, 128.44, 128.42, 128.09, 127.90, 126.65, 126.56, 123.51, 123.37, 119.91, 116.16, 59.02, 53.05, 52.65, 45.78, 42.13.

[0243] Example 14

[0244] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 14 R 1 =3-Cl, R 2=H, chemical name (E)-1-(4-(3-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(3-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0245]

[0246] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0247] As in the first step of Example 1.

[0248] Step 2: Synthesis of 1-(3-chlorobenzyl)piperazine (intermediate 2m)

[0249]

[0250] As in step 2 of Example 1, the difference is that 3-chlorobenzyl chloride is used as the reactant.

[0251] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0252] As in step 3 of Example 1.

[0253] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0254] As in step four of Example 1.

[0255] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0256] As in step 5 of Example 1.

[0257] Step 6: (E)-1-(4-(3-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I) 14 Synthesis of )

[0258] As in step 6 of Example 1, the difference is that 1-(3-chlorobenzyl)piperazine is used as the reactant.

[0259] Target compound I 14 It is a white solid with a yield of 75%. 1H NMR (400MHz, CDCl3) δ8.72 (d, J=2.0Hz, 1H), 8.42 (dd, J=7.6, 2.4Hz, 1H), 8.01 (dd, J=8.6, 2.7Hz, 1H), 7.96-7.87 (m, 1H), 7.74-7.64 (m, 3H), 7.47 (q, J=7.0Hz, 1H), 7.35 (q, J=6.7Hz, 1H), 7.29 (s, 1H), 7.26-7.12 (m, 4H), 6.87 (d, J=15.6Hz, 1H), 3.61 (s, 2H), 3.49-3.32 (m, 4H), 2.29 (d, J=55.8Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.72, 165.00, 154.18, 151.80, 150.75, 139.88, 136.13, 134.33, 134.27, 130.68, 129.61, 128.96, 12 8.64, 128.47, 128.08, 127.90, 127.47, 127.09, 126.57, 123.50, 123.37, 119.85, 116.15, 62.10, 53.00, 52.62, 45.69, 42.07.

[0260] Example 15

[0261] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 15 R 1 =4-Cl, R 2 =H, chemical name (E)-1-(4-(4-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(4-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0262]

[0263] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0264] As in the first step of Example 1.

[0265] Step 2: Synthesis of 1-(4-chlorobenzyl)piperazine (intermediate 2n)

[0266]

[0267] As in step 2 of Example 1, the difference is that 4-chlorobenzyl chloride is used as the reactant.

[0268] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0269] As in step 3 of Example 1.

[0270] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0271] As in step four of Example 1.

[0272] Step 5: Synthesis of (2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0273] As in step 5 of Example 1.

[0274] Step 6: (E)-1-(4-(4-chlorobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I) 15 Synthesis of )

[0275] As in step 6 of Example 1, the difference is that 1-(4-chlorobenzyl)piperazine is used as the reactant.

[0276] Target compound I 15 It is a white solid with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.43 (dd, J=8.3, 1.5Hz, 1H), 8.01 (d, J=8.4Hz, 1H), 7.92 (ddd, J=8.5, 6.9, 1.5Hz, 1H), 7.75-7.65 (m, 3H), 7.48 (td, J=7.7, 1.6Hz , 1H), 7.35 (td, J=7.6, 1.3Hz, 1H), 7.29 (d, J=8.2Hz, 2H), 7.23 (t, J=7.5Hz, 3H), 6 .87 (d, J=15.6Hz, 1H), 3.61 (s, 2H), 3.40 (d, J=9.6Hz, 4H), 2.29 (d, J=48.7Hz, 4H); 13C NMR (101MHz, CDCl3) δ166.74, 165.00, 154.19, 151.80, 150.75, 136.18, 136.11, 134.34, 133.02, 130.70, 130.31, 128.64, 1 28.50, 128.39, 128.08, 127.89, 126.58, 123.52, 123.37, 119.82, 116.16, 77.24, 76.97, 61.97, 53.03, 52.56, 45.72, 42.07.

[0277] Example 16

[0278] The cinnamamide derivative I containing quinazoline and piperazine units of the present invention 16 R 1 =4-NO2, R 2 =H, chemical name (E)-1-(4-(4-nitrobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one, English name (E)-1-(4-(4-nitrobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one, structural formula as follows:

[0279]

[0280] Step 1: Synthesis of piperazine monohydrochloride (intermediate 1)

[0281] As in the first step of Example 1.

[0282] Step 2: Synthesis of 1-(4-nitrobenzyl)piperazine (intermediate 2o)

[0283] As in step 2 of Example 1, the difference is that 4-nitrobenzyl chloride is used as the reactant.

[0284] Step 3: Synthesis of quinazolin-4(3H)-one (intermediate 3a)

[0285] As in step 3 of Example 1.

[0286] Step 4: Synthesis of 4-chloroquinazoline (intermediate 4a)

[0287] As in step four of Example 1.

[0288] Step 5: Synthesis of 3-(2-(quinazolin-4-oxo)phenyl)acrylic acid (intermediate 5a)

[0289] As in step 5 of Example 1.

[0290] Step 6: (E)-1-(4-(4-nitrobenzyl)piperazin-1-yl)-3-(2-(quinazolin-4-oxy)phenyl)prop-2-en-1-one (target compound I) 16 Synthesis of )

[0291] As in step 6 of Example 1, the difference is that 1-(4-nitrobenzyl)piperazine is used as the reactant.

[0292] Target compound I 16 It is a white solid with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.43 (dd, J=8.4, 1.4Hz, 1H), 8.21-8.14 (m, 2 H), 8.00 (d, J=8.4Hz, 1H), 7.91 (ddd, J=8.4, 6.9, 1.5Hz, 1H), 7.75-7.64 (m, 3H) , 7.52-7.44 (m, 3H), 7.35 (td, J=7.6, 1.2Hz, 1H), 7.24 (d, J=1.2Hz, 1H), 6.87 (d , J=15.6Hz, 1H), 3.63 (s, 2H), 3.54 (s, 2H), 3.43 (s, 2H), 2.33 (d, J=40.4Hz, 4H); 13 C NMR (101MHz, CDCl3) δ166.74, 165.05, 154.17, 151.81, 150.78, 147.33, 145.64, 136.25, 134.33, 130.76, 129.42, 128.59, 1 28.34, 128.07, 127.90, 126.58, 123.63, 123.52, 123.37, 119.68, 116.16, 77.26, 76.99, 61.85, 53.17, 52.70, 45.67, 42.02.

[0293] Application performance testing

[0294] Test methods for inhibiting the activity of plant pathogenic fungi:

[0295] Using agricultural fungicides hymexazol and cyazofamid as positive controls, the inhibitory effects of the target molecules at a concentration of 50 μg / mL on *Botrytis cinerea* (tomato causal agent), *Sclerotinia sclerotiorum* (rapeseed sclerotinia), *Fusarium graminearum* (wheat scab), and *Rhizoctonia solanis* (rice sheath blight) were determined using the mycelial growth rate method. 200 g of potato slices were added to 800 mL of boiled secondary water and boiled until easily broken with a glass rod. The mixture was filtered through gauze and the filtrate was reserved. Separately, 200 mL of secondary water was measured, 20 g of agar powder was added, and the mixture was stirred well. The filtrate from the previous step was then added, and the secondary water was added until a final volume of 1 L was reached. After boiling, 20 g of glucose was added, and the mixture was stirred well and dispensed into Erlenmeyer flasks to obtain PDA medium. After sterilizing freshly prepared PDA medium at 121℃ for 20 min, 100 μL of drug-containing DMSO was added to 45 mL of sterilized and still-warmed PDA medium using a 200 μL pipette. After mixing, the drug-containing medium was evenly transferred to three disposable culture dishes and allowed to cool naturally under UV light. Once cooled, 5 mm diameter mycelial discs were inoculated into the center of each disposable culture dish, and then transferred to a 25℃ incubator for inverted cultivation in the dark. When the colony diameter of the blank control reached 70-80 mm, the colony diameter of each treatment group was measured using the cross-sectional method. The inhibition rate of the corresponding treatment group against plant pathogenic fungi was then calculated based on the colony diameters obtained from the blank and drug-treated groups. The test results are shown in Table 1.

[0296] Table 1 Compounds I1-I 16 Inhibitory activity against plant pathogenic fungi at a concentration of 50 μg / mL

[0297]

[0298]

[0299] Table 1 shows that most target molecules exhibited relatively ideal inhibitory effects against *Botrytis cinerea* (tomato causal agent), *Sclerotinia sclerotiorum* (rapeseed causal agent), *Fusarium graminearum* (wheat scab), and *Sheath blight* (rice wilt) at a concentration of 50 μg / ml. Among them, target molecules I1, I5, I8, and I... 10 I 11 I 12 I 13 I 15 and I 16At a concentration of 50 μg / mL, the inhibition rates against *Botrytis cinerea* var. *tomatoides* were 80.5%, 80.4%, 82.4%, 80.0%, 80.1%, 82.4%, 80.7%, 80.0%, and 90.6%, respectively, significantly higher than that of hymexazol at the same concentration (62.2%). Target molecule I 13 I 15 and I 16 At 50 μg / mL, it also showed significant inhibitory activity against *Sclerotinia sclerotinia*, with inhibition rates of 72.4%, 68.1%, and 97.2%, respectively, which was superior to the inhibition rate of hymexazol against *Sclerotinia sclerotinia* at this concentration (65.1%). Target molecules I1, I3, I4, I5, I6, I9, I... 10 I 15 and I 16 At a concentration of 50 μg / ml, the inhibition rate against Fusarium graminearum, the causal agent of wheat blight, ranged from 51.4% to 63.6%, showing slightly better activity than hymexazol (50.7%) and cyazofamid (31.1%). Furthermore, the target molecules I2, I4, I5, I8, I9, and I... 10 I 13 I 14 and I 15 At a concentration of 50 μg / ml, it also showed a certain inhibitory effect on rice sheath blight pathogens, with inhibition rates exceeding 50%. It is worth noting that compound I... 16 At 50 μg / mL, the inhibition rates against Botrytis cinerea, Sclerotinia sclerotiorum, and Fusarium head blight of tomatoes reached 90.6%, 97.2%, and 63.6%, respectively, which were superior to those of hymexazol (62.2%, 65.1%, and 50.7%) and cyazofamid (87.4%, 89.5%, and 31.1%).

Claims

1. A cinnamamide derivative containing quinazoline and piperazine units, characterized in that, The structural formula is shown in Formula I: In the formula: R 1 Selected from hydrogen, 2-methyl, 3-methyl, 4-methyl, 3-methoxy, 3-bromo, 4-bromo, 4-fluoro, 3-fluoro, 3-cyano, 2-chloro, 3-chloro, 4-chloro, 4-nitro; R 2 Selected from hydrogen, 3-(3-methylbut-2-en-1-yl)-4-methoxy.

2. The method for preparing the cinnamamide derivative containing quinazoline and piperazine units according to claim 1, characterized in that, Piperazine reacts with piperazine dihydrochloride in hot ethanol, followed by sequential reactions with different benzyl chlorides and sodium hydroxide solutions to obtain the corresponding monosubstituted piperazines. Subsequently, methyl anthranilate reacts sequentially with formamide, thionyl chloride, coumarin molecules hydrolyzed with sodium hydroxide, and the monosubstituted piperazine to obtain the cinnamamide derivative I containing quinazoline and piperazine units. The synthetic route is as follows:

3. The application of the cinnamamide derivative containing quinazoline and piperazine units as described in claim 1 in the prevention and control of tomato gray mold, rapeseed sclerotinia stem rot, wheat scab, or rice sheath blight.

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